In keeping with a mission of NIAAA to increase the understanding of normal and abnormal biological functions and behavior relating to alcohol use, the goal of the proposed studies is to advance knowledge about the unique neuroadaptation of the human brain to the injury caused by chronic alcoholism. In this proposal alcoholic brain damage is viewed as a disorder of neuroconnectivity with structural and functional concomitants. Many brain networks and systems subserving specific functions have well defined architecture. It has recently been recognized that there are also brain networks without a known neuroanatomy that reflect intrinsic brain functioning and are demonstrable only with functional connectivity imaging. This project will apply advanced neuroimaging to interrogate the disruption of neuroconnectivity in alcoholics and their potential compensatory neuroadaptation. Quantitative measurement of brain white matter microstructure will be assessed by fiber tracking with diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI); scalp-recorded EEG and event- related potentials (ERPs) will reflect the synchrony of brain electrical potentials across large cerebral networks and their connectivity; intrinsic and task-related functional connectivity will be identified with functional MRI (fMRI and fcMRI) using both blood oxygen level dependent (BOLD) and noninvasive cerebral blood flow (CBF) acquired with Pulse Continuous Arterial Spin Labeling (PCASL). Knowledge of the extent and specificity of connectivity dysfunction in alcoholism forms a basis for targeting specific rehabilitation strategies and consideration of new treatment approaches. The proposal will study alcoholic men and women and age- and sex-matched nonalcoholic comparison groups with three specific aims, each with explicit testable hypotheses: Specific Aim 1: To probe intrinsic functional networks using resting state fcMRI and PCASL and task- activated fMRI and PCASL to measure changes in regional BOLD and CBF activity. Specific Aim 2: To probe neurocircuitry with resting EEG coherence and ERP time-frequency analyses of a visual GO/NOGO task and multiple component analyses of a conflict resolution task. Specific Aim 3: To determine the extent of alcoholism-induced degradation of white matter circuitry connecting nodes of the task-activated and intrinsic networks using HARDI quantitative fiber tracking. Exploratory analyses will examine the role of age, sex, family history of alcoholism, length of sobriety, smoking, education, intelligence, and impulsivity in adaptation to alcoholism-induced brain connectivity disruption. PUBLIC HEALTH RELEVANCE: Advanced structural, functional, and electrophysiological neuroimaging of brain connectivity networks will be used to further knowledge about the unique neuroadaptation of the human brain to the injury caused by chronic alcoholism. Knowledge of the extent and specificity of brain dysfunction in alcoholism forms a basis for targeting specific rehabilitation strategies and consideration of new treatment approaches.